| Brown Norway (BN) rats are susceptible to Sendai virus-induced chronic airway inflammation that results in fibrosis and functional abnormalities resembling asthma. Fischer (F344) rats are resistant to these virus-induced changes and have earlier viral clearance, increased expression of Th-1 cytokines (e.g., interferon-γ, IFN-γ), and do not develop pulmonary function abnormalities. In contrast, BN rats are Th-2 type cytokine responders (e.g., interleukin-4, IL-4) and have delayed viral clearance. Due to the critical role of interleukin-2 (IL-12) in regulating the IFN-γ cytokine response in intracellular infections, I hypothesized that virus-resistant F344 rats are higher IL-12 gene responders than BN rats. Levels of IL-12 p40 messenger (mRNA) were measured by real-time polymerase chain reaction (RT-PCR) and IL-12 protein was detected by lung homogenate enzyme-linked immunosorbent assay (ELISA) at several time points after viral inoculation. Although virus infection resulted in increased IL-12 production in both strains, F344 rats had significantly more IL-12 p40 mRNA than BN rats at 0–3 days (early) after virus inoculation (p < 0.05).{09}Furthermore, IL-12 total protein levels were elevated in F344 rats as early as 2 days following viral challenge, and the numbers of IL-12 p40 protein expressing cells were also significantly increased in their bronchioles at 2 and 3 days following Sendai inoculation (p < 0.05). To evaluate the potential protective role of IL-12 in virus-induced airway injury, BN rats were given IL-12 intraperitoneally at either the time of (day 0) or two days after viral inoculation (day 2). In contrast to infected rats given saline, infected rats treated with IL-12 at day 0 had 22.1% lower levels of chronic airway inflammation, 23.8% lower levels of airway fibrosis, and 42% and 62.5% decrease in bromodeoxyuridine (BrdU)-labeled fibroblasts at 10 and 14 days after inoculation respectively (p < 0.05). Day 0 treated BN rats had a 4-fold increase in the pulmonary IFN-γ mRNA and a 77% increase in IFN-γ protein as compared to saline-treated, virus-inoculated controls. In contrast, day 2 IL-12 treatment induced a 20% increase in bronchiolar airway wall thickness, a 12.5% increase in BrdU-labeled fibroblasts at 14 days after inoculation, and an increase in pulmonary IL-4 mRNA (p < 0.05). The results are consistent with the hypothesis that resistance to virus-induced airway damage in F344 rats is due, at least in part, to their high virus-induced IL-12 gene expression. |
